Background:
Despite improvement in survival of newly diagnosed adult ALL, the results of relapsed/refractory disease are still poor, with long term survival of < 10%. Blinatumomab, a bispecific ...monoclonal antibody directed against CD19/CD3 show clinical activity against relapsed/refractory B-ALL as well as in MRD positive patients. Given in a continues 28 days infusion, and its unique side effects profile are potential drawbacks to using blinatumomab in routine care. We report our initial experience with blinatumomab in widespread use, in real-world experience.
Methods:
Data from adult patients with B-ALL/B-LBL treated with blinatumomab in 4 hospitals in Israel was collected. Blinatumomab was given at the standard dose of 9 mcg/day in the first week of the first cycle, and 28 mcg/day thereafter for 28 days cycles, repeated every 6 weeks. Safety data including cytokine release and neurological symptoms was collected. Efficacy outcome included overall and complete response rates, overall survival, and leukemia free survival.
Results:
13 patients are included in this analysis, median age 51.6 years (range 28.9-80.3) 7 male and 6 females. Diagnoses were B-ALL in 10, Ph+ B-ALL in 2, and B-LBL in 1 patient. Median time from diagnosis to blinatumomab treatment was 9.8 months (range 3.4-26.3), and 12/13 patients received blinatumomab for hematological relapse with 1 patient receiving treatment due to severe fungal infection and inability to continue standard chemotherapy or proceeding to SCT. Four patients (30.7%) received blinatumomab after allogeneic SCT. Three patients (23%) had CNS disease at the time of relapse. Blinatumomab was given as first salvage in 7, and after prior salvage in 6 patients. Median number of blinatumomab cycles were 1 (range 1-6), and patients spent on average 18.9 days in-hospital, and 18.8 days as outpatients during the treatment period.
Response was evaluable in 12 patients with 5/12 patients achieving CR and 1 patient maintaining a previously achieved CR. CR was achieved in 2/2 Ph+ ALL patients, 1/4 patients relapsing after SCT and 1/3 patients with CNS disease at relapse. Following blinatumomab, 4 patients received allogeneic SCT, 1 in CR, 2 failing blinatumomab and entering CR after CAR-T therapy within a clinical trial and 1 after combination chemotherapy.
Non-hematological side effects consisted of neurological symptoms in 1 (grade 2), GI symptoms in 1 (grade 3), infection in 1 (grade 3) and cytokine release syndrome in 3 patients (2-grade 2; 1-grade 4).
At a median follow up of 13.3 months (range 1-20.6), 8 (62%) patients are alive, 6 (46%) in CR. Reasons for death included infection in 3 and disease progression in 2 patients. No patient died during blinatumomab administration. Median LFS is 8.7 months and median OS was not reached.
Conclusions:
The current cohort show a slightly higher CR rate and similar OS compared to the TOWER and ALCANTARA trials. Treatment with blinatumomab was safe, with manageable toxicity profiles. This, however, was achieved at a cost of prolonged hospitalizations in the majority of patients.
Ofran:Novartis: Other: Served on a Novartis advisory board.
Background
Newly diagnosed AML patients who cannot tolerate intensive chemotherapy have limited treatment options and poor long-term outcomes. Recently, the U.S FDA approved combination of ...venetoclax, an anti BCL-2 oral agent with hypomethylating agents or LDAC for this patient population based on a series of phase 1b/2 trials showing high CR/CRi rates.
Methods
Venetoclax combinations are available in Israel since January 2019 following approval and reimbursement by the health authority. Medical centers participating in the Israeli Acute Leukemia Group were approached for data collection. We specifically sought to collect safety parameters, and short term outcomes were a secondary outcome in this report.
Results
35 patients from 5 medical centers are included in this analysis. Median age was 80 years (range 62-95), 16 males and 18 females. Diagnoses were de novo AML in 17, secondary AML (to MDS/MPN) in 16, and t-AML in 2 patients. High risk AML seen in 15 patients, followed by intermediate (n=11) and favorable (n=7) risk categories (data NA in 2). Median ECOG PS was 0 (7 with ECOG≥2). Patients were considered not eligible for intensive therapy due to age (n=28), comorbidity (n=10), poor performance status (n=4) or other reasons (n=3).
Median bone marrow blasts at diagnosis was 36% (range 8-90%). The median WBC, ANC, Hb and PLT were 8.0 K/µl (range 0.9-108), 1.7 K/µl (range 0.3-16.4), 8.6 g/dL (range 4.4-13.9) and 77 K/µl (range 9-306), respectively. Median LDH, uric acid and creatinine levels were 1.5 times ULN (range 1-5), 5.3 mg/dl (range 2.3-16), and 0.98 mg/dl (range 0.73-2.25), respectively.
The median time from AML diagnosis to start of treatment was 1 month (range 0-6). Venetoclax was combined with azacitidine in most cases (32/35); 2 patients received LDAC as a combination, and 1 additional patient received one cycle with LDAC followed by azacitidine combination. At the time of data analysis, treatment was given for a median 3 cycles (range 1-10). Azacitidine was most commonly administered in a 5+2 regimen (20/33, 61%), followed by a 7 day regimen (12/33, 37%). One patient received 5 days courses. Venetoclax was given with a short ramp up (median 3 days, range 2-11) and then at a median daily dose was 400 mg (range 200-400). Dose reductions occurred in 14 (40%) patients, mainly for potential drug-drug interactions. Therapy was started during hospitalization in 16 patients, with a median hospitalizations duration of 7 days (range 4-30); 12 patients were treated with hydroxyurea for cytoreduction prior to commencing venetoclax combination.
Treatment was associated with side effects in all patients, including grade 3-4 neutropenia in 26 (84% of evaluable patients) and grade 3-4 thrombocytopenia in 18 patients (58% of evaluable patients). The most common non-hematologic side effects were infections; Febrile neutropenia in 16 (46%) and non-febrile infections in 19 patients (54%)- 2 pneumonia, 1 periorbital cellulitis, 1 herpes zoster, and 1 pulmonary aspergillosis. Gastrointestinal side effects occurred in 9 (26%), 1 grade 3, and tumor lysis syndrome occurred in 5 patients (14%), 1 grade 4. Cardiac adverse events were reported in 2 and 1 patient experienced ischemic stroke.
Responses were assessed after 2 treatment courses and are available in 22 patients, with 15 patients (68%) achieving CR/CRi. Response (CR+CRi) was achieved in 55%, 70% and 50% of patients with high, intermediate and favorable risk groups, respectively. Complete response was seen in 2/2 patients with available data, with prior hypomethylating agents.
At a median follow up of 4.1 months (range 0.2-13), 25 patients are alive (70%), with 13/16 (81%) patients with evaluable data in CR/CRi. The most common causes for death were infectious complications (n=4 including 1 in CR), and disease progression (n=3). The median EFS are 3.8 months, and median OS 13 months.
Conclusions
Treatment with venetoclax combinations in AML patients ineligible for intensive treatment outside of clinical trials was associated with high rates of hematologic and non-hematologic side effects, including tumor lysis syndrome in 14% of patients, which is higher than reported in the original trials. Although the follow up in this cohort is rather short, the CR/CRi rates are similar to those achieved in published clinical trials and encouraging.
Wolach:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaker; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaker.
Functional role of CXCR4 in chronic myelogenous leukemia (CML) progression was evaluated. Elevated CXCR4 significantly increased the in vitro survival and proliferation in response to CXCL12. CXCR4 ...stimulation resulted in activation of extracellular signal-regulated kinase (Erk)-1/2, Akt, S6K, STAT3, and STAT5 prosurvival signaling pathways. In accordance, we found that in vitro treatment with CXCR4 antagonist BKT140 directly inhibited the cell growth and induced cell death of CML cells. Combination of BKT140 with suboptimal concentrations of imatinib significantly increased the anti-CML effect. BKT140 induced apoptotic cell death, decreasing the levels of HSP70 and HSP90 chaperones and antiapoptotic proteins BCL-2 and BCL-XL, subsequently promoting the release of mitochondrial factors cytochrome c and SMAC/Diablo. Bone marrow (BM) stromal cells (BMSC) markedly increased the proliferation of CML cells and protected them from imatinib-induced apoptosis. Furthermore, BMSCs elevated proto-oncogene BCL6 expression in the CML cells in response to imatinib treatment, suggesting the possible role of BCL6 in stroma-mediated TKI resistance. BKT140 reversed the protective effect of the stroma, effectively promoted apoptosis, and decreased BCL6 levels in CML cells cocultured with BMSCs. BKT140 administration in vivo effectively reduced the growth of subcutaneous K562-produced xenografts. Moreover, the combination of BKT140 with low-dose imatinib markedly inhibited tumor growth, achieving 95% suppression. Taken together, our data indicate the importance of CXCR4/CXCL12 axis in CML growth and CML-BM stroma interaction. CXCR4 inhibition with BKT140 antagonist efficiently cooperated with imatinib in vitro and in vivo. These results provide the rational basis for CXCR4-targeted therapy in combination with TKI to override drug resistance and suppress residual disease.
Patients hospitalized with pneumonia may require packed red blood cell (RBC) transfusion during their hospital stay. Patient survival may be associated with the transfusion trigger. These patients ...may need a higher hemoglobin (Hb) trigger than that suggested by the AABB guidelines (7 g/dL).The objective of this study was to evaluate the association between the initial transfusion Hb trigger and in-hospital mortality.A historical cohort study of all patients hospitalized in an internal medicine ward between 2009 and 2014 with pneumonia, who received at least 1 unit of RBC, was evaluated. The primary outcome was all-cause in-hospital mortality.One hundred males and 77 females with a median age of 80 (interquartile range 71-87) years were included. The median Hb trigger was 8.10 g/dL. Mortality rate was 56% in patients with Hb trigger ≤7 g/dL, 43.8% in Hb trigger 7 to 8 g/dL, and 29.5% in Hb trigger >8 g/dL (P = .045). Patients in the 3 Hb trigger categories did not differ in age, sex, comorbidities, albumin, creatinine, C-reactive protein, white blood cells, and platelet counts. The result of a multivariate analysis showed that only lower Hb trigger (odds ratio OR≤ 7vs.>8 = 5.24, OR7-8vs.>8 = 2.13, P = .035) and higher neutrophil count (P = .012) were associated with increased in-hospital mortality.In conclusion, a lower transfusion trigger is associated with increased risk for in-hospital mortality in patients hospitalized with pneumonia requiring RBC transfusion.
Data from 11 Israeli centers, where venetoclax was used for relapsed/refractory AML after intensive chemotherapy, were retrospectively collected. During 2016-2019, forty patients were identified. ...Median age was 67 years (21-82), 60% males, median of 2(1-4) prior lines of treatment and 42% relapsed after allogeneic transplant. 62.5% of the patients received the venetoclax with hypomethylating agents and 22.5% with low dose cytarabine. Median follow-up was 5.5 months. Of the 29 patients who survived for more than two cycles of therapy, 22 (76%) achieved neutrophil recovery and 59% (n = 17) recovered also their platelet count. In 15 (52% of those who survived > 2 months), CR/CRi was confirmed by bone marrow examination. The median OS from venetoclax initiation of all the patients and of those who survived more than 2 months was 5.5 and 6.5 months, respectively. In conclusion, this study demonstrates that venetoclax is safe and active also in AML patients with advanced disease.
This national Israeli multicenter retrospective study aimed to characterize the clinical course of COVID-19 infection among patients with hematological malignancies, with special emphasis on ...treatment efficacy and outcome. Clinical and laboratory data from haemato-oncological patients diagnosed with COVID-19 from 16 medical centers were centrally reported. Multivariate regression analyses were used to determine variables associated with severe disease, hospitalization, and mortality. In total, 313 patients were included: 103 (35.7%) developed severe/critical respiratory infection, 178 (61.4%) were hospitalized, and 60 (20.0%) died. Age > 70 years was associated with severe/critical disease (p = 0.036) and mortality (p = 0.023), hypertension with severe/critical disease (p = 0.046) and hospitalization (p = 0.001), active haemato-oncological treatment with hospitalization (p = 0.009), and remdesivir treatment was associated with decreased mortality (p = 0.021). Convalescent plasma, enoxaparin, and corticosteroids resulted in no clinical benefit. In conclusion, COVID-19 infection seems particularly severe in patients with hematological malignancies, and of all examined therapies, remdesivir appears to be the most effective.
: Objectives: Central retinal vein occlusion (CRVO) and central retinal artery occlusion (CRAO) are common disorders associated with risk factors for atherosclerosis. Protein Z is a cofactor for the ...inactivation of activated factor X (Xa) by the protein Z dependent protease inhibitor. Protein Z deficiency was recently linked to increased risk of arterial thrombosis. We investigated whether CRVO and CRAO are associated with low protein Z levels. Patients and methods: Patients with CRVO, CRAO or recurrent branch retinal vein occlusion were recruited to the study. Protein Z level, lupus anticoagulant (LAC), anticardiolipin antibodies (ACA) and activated protein C resistance (APCR) were determined in plasma from patients (n = 36) and healthy controls (n = 42). Results: Thirty patients in the study group had traditional risk factors for retinal vessel occlusion and six patients had none. There was no significant difference in protein Z levels between the whole study group patients and controls (1995 ± 810 vs. 2010 ± 603 ng/mL, P = 0.922). However, patients with no risk factors for retinal vessel occlusion had significantly lower protein Z levels than controls (1379 ± 682 vs. 2010 ± 603 ng/mL, P = 0.022). Positive LAC was found in six patients and one control subject (P = 0.04). There were three patients and one control subject with abnormal APCR (P = 0.3) and none with positive ACA. Low protein Z level (lower than fifth percentile of control) was not associated with the presence of LAC or APCR. Conclusion: Low protein Z level may be another risk factor for retinal vessel occlusion in patients without traditional risk factors for these disorders.
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